Use of serotonergic compound for a method of treatment of hot flushes in post-menopausal women

ABSTRACT

The present invention relates to a method of treatment of hot flushes with a 5-HT 2C  receptor agonist and in particular to the use of the selective 5-HT 2C  receptor agonists 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or pharmaceutically acceptable acid addition salts thereof for the manufacture of a pharmaceutical formulation adapted for the treatment of hot flushes.

This application is a divisional of U.S. application Ser. No.10/039,455, filed on Oct. 29, 2001, now U.S. Pat. No. 6,498,184.

FIELD OF THE INVENTION

The invention relates to the use of a serotonergic compound for thetreatment of hot flushes.

BACKGROUND OF THE INVENTION

The most well-known complaints of the (post)-menopausal syndrome are dueto changes in temperature regulation, causing sudden crises of feelingsof excessive body heat (hot flushes). These symptoms are highlydisturbing for a large proportion of menopausal women, leading totherapy requests to the medical profession. Usually, replacement ofestrogens is selected as remedy. Less commonly and more recentlyexplored is the selection of non-hormonal compounds as medicine fortreating hot flushes. For example, the use of serotonergic uptakeinhibitors and serotonin (=5-hydroxy-tryptophan=5-HT) antagonists forthe treatment of hot flushes is discussed in Berendsen, Maturitas Vol36, pp 155–164, 2000. Some beneficial effects of 5-HT_(2A) antagonistsand serotonin uptake inhibitors were reported. The beneficial effect ofthe serotonin reuptake inhibitors sertraline and paroxetine weredescribed in Plouffe et al., Delaware Medical Journal 69: pp 481–482,1997, Roth and Scher, Psycho-Oncology 7, pp 129–132, 1998, and Stearnset al., Annals of Oncology 11, pp 17–22, 2000.

SUMMARY OF THE INVENTION

It has now been found that an agonist for 5-HT_(2C) receptors in anorganism can be used for a method of treatment of hot flushes.

DETAILED DESCRIPTION OF THE INVENTION

Unexpectedly, these 5-HT_(2C)-agonists produce better results thanSSRI's against hot flushes in view of the extent to which side effectsare compensated for by efficacy.

Thus, the invention provides for a method of treatment of hot flusheswith a 5-HT_(2C) receptor agonist. In particular, a selective 5-HT_(2C)receptor agonist is preferred. A selective 5-HT_(2C) receptor agonist inthe context of the description of this invention means a 5-HT_(2C)receptor agonist which is more active as agonist on 5-HT_(2C) receptorsthan on other 5-HT receptor subtypes, such as 5-HT_(1A), 5-HT_(2A)and/or 5-HT₃ receptors. The selective 5-HT_(2C) receptor agonist shouldpreferably be such that it is at least 5 times more active on 5-HT_(2C)receptors than on the other serotonin receptors. The 5-HT agonistsdescribed in EP 370 560 are particularly suitable for the use of thisinvention. Specifically1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and itspharmaceutically acceptable acid addition salts have the most desirableproperties out of this group for the use of this invention. Morepreferred is the use of a 5-HT_(2C) agonist being at least 10 times moreactive on 5-HT_(2C) receptors relative to 5-HT_(2A) receptors. Mostpreferred is the use of the azetidines or pyrrolidine compoundsdisclosed in EP863136 for use in the treatment of hot flushes, and inparticular the compound(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or itspharmaceutically acceptable acid addition salts described in thatdisclosure.

Since the treatment of the present invention is not based on hormonereplacement these treatment agents are preferably used in thosecircumstances were treatment with a hormone or a hormone receptoragonist bears higher risks. Therefore, an aspect of this invention isthat it makes a treatment available for hot flushes in patients at riskfor hormone dependent tumour growth. Such patients are the group ofpatients with ovariectomy in view of estrogen dependent tumour growth.Another aspect of the invention is that it makes a treatment availablefor hot flushes in patients with adverse feminizing responses toestrogens. In particular, male patients functionally orpharmacologically castrated for the purpose of removing endogenoushormones can be treated for hot flushes with 5-HT_(2C)-agonists.

Hot flushes not only occur as complaint during menopause, but also incertain women during specific points in time of the menstrual cycle, forexample before and during the days of menstruation. It is an aspect ofthis invention that hot flushes in those circumstances can be very wellnon-hormonally treated with a 5-HT_(2C) agonist.

The terms used in this description have the meaning according to commonunderstanding of these terms. The accepted use of the terminology toindicate serotonin receptor subtypes is for example used in Barnes andSharp, Neuropharmacology 38, pp 1083–1152, 1999. A serotonergic compoundis a compound which directly or indirectly, for example as agonist or asserotonin reuptake inhibitor activates serotonin receptors in anorganism. An agonist for a receptor is a compound which produces aneffect caused by conformational changes of the receptor by directbinding to the receptor. For the 5-HT_(2C) receptor the agonist mimicksat least partially the effect of serotonin. Thus, a partial agonist isexplicitly included within the scope of this invention. It is in manycircumstances beneficial to use a partial agonist rather than a fullagonist. The former might be less efficacious but may have less risk forfull-blown adverse overdose effects.

Determination of selectivity of a receptor agonist can be done bymethods well known in the art. The basic technique is with bindingexperiments in which the compound is tested for binding affinity to thesubtypes of receptors. Alternatively, selectivity can be determined within vitro expression systems in which a biochemical parameter, such ascyclic adenosine monophosphate or phosphoinositol production orinhibition is used to determine receptor activation by an agonist. Invivo methods can also be used when selective models for testing receptorstimulation are available. Some differences in the selectivity resultsobtained with these methods can occur. Usually, and under the conditionthat the test is accepted as reliable, the in vivo selectivity is thepreferred indicator for determination of selectivity of a compound overin vitro methods. Results with in vitro expression of receptor activityare in turn more preferred for determination of the selectivity thanbinding experiments. For a suitable collection of techniques todetermine the properties of a 5-HT_(2C) agonist reference is made toMartin et al., 5-HT_(2C) receptor agonists: Pharmacologicalcharacteristics and therapeutic potential. J. Pharmacol & ExperimentalTherapeutics 286: 913–924, 1998

The present invention further includes the use of a 5-HT_(2C)-agonistfor the manufacture of a medicament for the treatment of hot flushes.

Suitable acid addition salts include hydrochloric, fumaric, maleic,citric or succinic acid, these acids being mentioned only by way ofillustration and without implied limitation. A preferred salt is thehydrochloric acid salt.

The amount of a 5-HT_(2C) agonist, also referred to herein as the activeingredient, which is required to achieve a therapeutic effect will, ofcourse, vary with the particular compound, the route of administrationand the age and other conditions of the recipient.

A suitable daily dose for any of the two compounds chemically namedabove will be in the range of 5 to 140 mg of the base per person perday, preferably in the range of 20 to 70 mg of the base per recipientper day. In the case of tolerance development, treatments can be furtheroptimalised by increasing the dose up to 5 times in the course of achronic treatment in humans. The desired dose may be presented as one,two, three or more sub-doses administered at appropriate intervalsthroughout the day.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical formulation.Accordingly, the present invention further provides a pharmaceuticalformulation for use in the treatment of hot flushes comprising a5-HT_(2C)-agonist, together with a pharmaceutically acceptable carrierthereof and optionally other therapeutic agents. The carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipients thereof. Theinvention further includes a pharmaceutical formulation, as hereinbeforedescribed, in combination with packaging material suitable for thepharmaceutical formulation, said packaging material includinginstructions for the use of the pharmaceutical formulation in thetreatment of hot flush.

Formulations include those suitable for oral, rectal, nasal, topical(including transdermal, buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous, intradermal andepidural) administration. The formulations may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al., Remington's PharmaceuticalSciences (18th ed., Mack Publishing company, 1990, see especially Part8: Pharmaceutical Preparations and their Manufacture). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Suchaccessory ingredients include those conventional in the art, such as,fillers, binders, diluents, disintegrants, lubricants, colorants,flavoring agents and wetting agents.

Formulations suitable for oral administration may be presented asdiscrete units such as tablets or capsules each containing apredetermined amount of active ingredient; as a powder or granulates; asa solution or suspension. The active ingredient may also be presented asa bolus or paste, or may be contained within liposomes ormicroparticles.

Formulations for rectal administration may be presented as a suppositoryor enema.

For parenteral administration, suitable formulations include aqueous andnon-aqueous sterile injection. The formulations may be presented inunit-dose or multi-dose containers, for example, sealed vials andampoules, and may be stored in a freeze dried (lyophilised) conditionrequiring only the addition of the sterile liquid carrier, for example,water prior to use.

Formulations suitable for administration by nasal inhalation includefine dusts or mists which may be generated by means of metered dosepressurised aerosols, nebulisers or insufflators.

Formulations may, for example, be presented in a suitable sustainedrelease form, for example, in a device such as the Minipump™.

The compounds according to the present invention are non-toxic.

The the compounds1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine, andtheir pharmaceutically acceptable acid addition salts may be prepared byany method known in the art for the preparation of a compound of similarstructure. Typically the compound1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine can be preparedby the methods described in EP 370 560, the contents of which areincorporated herein by reference, whereas the compound(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine and itspharmaceutically acceptable acid addition salts can be prepared by themethods described in EP863136, the contents of which are incorporatedherein by reference.

The following example is for illustration and should not be consideredto be limiting in anyway:

EXAMPLE

A test for demonstration of the effect of compounds on an acuteincrement of body heat production representative for hot flushes inhumans is based on telemetric body temperature measurements in freelymoving rats.

Method

Male rats (HSD/Cpb:WU, Harlan Sprague Dawley, Zeist, The Netherlands),weighing 350–480 g, were used. The rats were implanted with a Physio TelTA11CTA-F40 Implant (Data Sciences International) under pentobarbitalanaesthesia. After surgery the rats were housed individually in a typeII clear Macrolon™ cage (23×17××14 cm). The cages were placed onreceivers (RLA 1020). After a recovery and adaptation period of at leastone week the rats were used for the experiments. On the experimentalday, body temperature, heart rate and locomotor activity was monitoredfor 30 minutes prior to injection of vehicle or test compound. Thisperiod provides a baseline core body temperature relative to which thechanges of body temperature after the manipulation of the rats forinjection are expressed. After 30 minutes the rats were injectedsubcutaneously with vehicle or test compound and the same parameterswere measured for at least 60 minutes. Immediately after injection thecore body temperature rises. Compounds inhibiting this rise intemperature reveal an inhibiting effect on acute body heat production.Results obtained with other parameters, such as the effect on heart rateand on locomotor activity are not presented here. 6 animals were usedfor measurement of each dose of compound

Compounds tested are:

-   -   1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine HCl,        which is indicated as Org 12962.    -   (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine        HCl, which is indicated as Org 37684.    -   Fluoxetine HCl

Data were analysed using Dataquest IV Data Acquisition System Ver 2.2.Compounds were dissolved in NaCl 0.9% (m/v) in water as vehicle forsubcutaneous injection.

TABLE 1 Effect of Org 37684 on temperature increments after manipulationof the rats relative to the body temperature during 30 minutes prior tothe manipulation. Org 37684 Org 37684 Org 37684 Org 37684 Dose: 0 mg/kg1.0 mg/kg 2.2 mg/kg 4.6 mg/kg Time¹  5 0.50² 0.29 0.41 0.00 10 0.69 0.680.47 −0.03 15 0.79 0.78 0.44 −0.13 20 0.80 0.58 0.40 −0.20 25 0.81 0.690.24 −0.14 30 0.60 0.63 0.13 −0.24 35 0.40 0.49 0.04 −0.24 40 0.41 0.40−0.05 −0.27 45 0.30 0.20 −0.09 −0.34 50 0.27 0.14 −0.21 −0.40 55 0.240.34 −0.26 −0.43 60 0.20 0.14 −0.25 −0.33 ¹is time after injection inminutes ²numbers in the tables represent absolute mean increments inbody temperature in ° C. for 6 rats relative to baseline during 30minutes prior to manipulation of the animals.

TABLE 2 Effect of Org 12962; explanation as for table 1 Org 12962 Org12962 Dose: 0 mg/kg 2.0 mg/kg Time  5 0.90 0.12 10 1.06 0.10 15 1.030.06 20 0.92 −0.03 25 0.93 −0.05 30 0.83 −0.14 35 0.81 −0.19 40 0.72−0.23 45 0.66 −0.19 50 0.65 −0.24 55 0.51 −0.25 60 0.41 −0.16

TABLE 3 Effect of fluoxetine; explanation as for table 1 FluoxetineFluoxetine Dose: 0 mg/kg 22 mg/kg Time  5 0.72 0.28 10 0.96 0.59 15 0.970.71 20 0.90 0.72 25 0.89 0.66 30 0.80 0.56 35 0.69 0.55 40 0.65 0.45 450.53 0.38 50 0.41 0.27 55 0.33 0.29 60 0.18 0.85Interpretation of Results:

The rise in body temperature of up to slightly less than 1° C. withinthe period of 60 minutes after manipulation for injecting the animalswas prevented by Org 12962 or by Org 37684, but not by fluoxetine. Theprevention of temperature rise was statistically significant for the two5-HT_(2C) agonists with the ANOVA/MANOVA Tukey HSD test on samplepoints. The results are interpreted to indicate that 5-HT_(2C) agonistscounteract acute increments in body temperature such as those whichoccur during a hot flush.

1. A method for the treatment of hot flushes in postmenopausal womencomprising the step of administering an effective amount of a selective5-HT_(2C) receptor agonist and a pharmaceutically acceptable carrier.